Highlights: Preparation and successfully testing of more than 400 sponge and bacterial extracts, and of a collection of >140 strains of marine bacteria from extreme marine environments (ISCAR collection) for antioxidant, antimicrobial, immunomodulatory, neuroprotective, anti-kinase, anti-osteoporosis and UV-protective activities

(ii)Screening and Bioactivity Identification

Highlights: Setting-up of a protein kinase platform, an Alzheimers’ disease cellular screening platformand a screening platform for antiprotozoan activity – Discovery and elucidation of the synergistic effect of quercetin and polyphosphate (polyP) on bone hydroxyapatite formation – Identification of triazines and pyrazoles as Amyloid β-42 inducers – Identification of a new target, the carbonic anhydrase, for compounds affecting bone formation and of a first activator of this enzyme, quinolinic acid, a sponge compound, and its combination with polyP-calcium as a regenerative material for treatment of osteoporosis-caused bone damage.

(iii)Isolation/Structure Elucidation

Highlights: Discovery of smenamide A and B, two highly cytotoxic hybrid peptide/polyketide marine sponge compounds, and of incisesterol A5 and A6, potent sponge agonists of PXR receptor, as well as of halomerol A, biosynthesized by a novel metabolic pathway – Isolation of new cytotoxic compounds from ascidians (phosphoeleganin and conithiaquinones A and B), and of two new depsipeptides, sulfinyltheonellapeptolide and theonellapeptolide, and a series of cyclotoxic macrolides, including the new compounds isoswinholide B and swinholide K, from Theonella swinhoei – Isolation, sequencing and NMR structure of the peptides, barrettide A and B, from the cold water sponge Geodia barretti– Isolation of a new antibiotic cyclic hexapeptide from two Icelandic thermophilic bacterial strains – Identification of a thiazinoquinone antimalarial lead compound – Discovery of spiroplakortone, plakortone Q and plakdiepoxide, novel polyketide-based metabolites from the sponge Plakortis simplex, active on nuclear receptors – Isolation of lacunalides A and B, novel trans-AT PKS derived polyketides – Discovery of a new antibacterial lipophilic cyclopeptide from a thermophilic bacteria.

(iv)Genomics

Highlights: Identification of new genes/cDNAs involved in carotenoid pathway – Demonstration of the interaction of retinal with the sponge peptide suberitine – Identification/characterization of two molecules of the sponge cryptochrome photoreception system, as well as of two marine sponge toxins of potential biomedical interest: a complement protein c8α-like polypeptide from the hexactinellid Crateromorpha meyeri and a cytolysin from the demosponge Dysidea avara – Isolation and expression of a sulfatase from D. avara – Cloning of the first poriferan laccase from Suberites domuncula, a copper-containing enzyme involved in the anti-bacterial defence system of sponges.

(v)Metagenomics and Gene Mining

Highlights: Identification of >50 gene clusters from uncultivated symbionts of marine sponges – Assembly of the misakinolide and psymberin gene cluster – Production of a new proteusin from a sponge symbiont and of polytheonamide analogs by heterologous expression – Identification of Swf, a new group of mono-modular type I PKS/FAS, which appears to be specifically associated to sponge symbionts.

(vi)Chemical Synthesis and Chemogenetics

Highlights: Identification of the 3D structural features of synthetic analogues of marine natural compounds, including plakortins (endoperoxides) and aplidinones (thiazinoquinone) with antimalarial activity – Elucidation of the mechanism of hydrolysis of 2-halotryptophans – Identification of the gene cluster responsible for the biosynthesis of merosterol – Chemical optimisation of the Leucettine scaffold – Establishment of the proof-of-concept in two mouse models for Leucettine L41 as an agent able to correct cognitive deficits associated with Down syndrome – Synthesis and successful folding of barrettide A.

(vii)Bioprocess Development and Scale-Up

Highlights: Successful establishment of the SustainCycle system for sponge culture – Successful scale-up of sponge primmorph culture – Development of a screening protocol for culturable marine microbial strains – Implementation of a protocol for the culture of Rhodothermus marinus in bioreactor with higher productivities.

(viii)Preclinical Studies

Highlights: Development of a novel microparticulate material with morphogenetic activity consisting of amorphous Ca-polyP – Development of electrospun fiber mats with this material and further bioactive components (retinoids) – Selection for further preclinical testing of the most advanced compounds of BlueGenics project: (i) retinol/polyP for wound healing and (ii) Leucettines for Alzheimer’s disease, the demonstration of activity of the electrospun mats with Ca-polyP and retinol on wound healing in mice (full excisional wound model) – Demonstration of the synergistic effect of retinol and Ca-polyP on collagen type III gene expression, as well as on the expression of leptin, leptin receptor and FABP4 – Pharmacokinetics and biodistribution of Leucettine L41 in Down syndrome mice model.